The present invention relates to a novel process for the reduction of alkyne compounds. The invention relates in particular to a process for the preparation of cyclohexene derivatives suitable as intermediates for the preparation of carotinoids.
A large number of the industrial carotinoid syntheses described in the literature, including the preparation of astaxanthine, proceed via cyclohexene intermediates which contain a Cxe2x89xa1C triple bond as well as one or more Cxe2x95x90C double bonds. To form a conjugated double bond system, this triple bond has to be partially reduced in a separate process step.
In the context of the astaxanthine synthesis described in DE-A-43 22 277, this partial reduction can take place with zinc/acetic acid in methylene chloride in the case of the alkynediol IVa. 
EP-A-0 005 748 relates to another process for the preparation of astaxanthine, in which the partial reduction of the alkynediol of formula IIIa is also carried out with zinc/acetic acid in methylene chloride. 
The disadvantage of the zinc/acetic acid reduction described is the inadequate selectivity of the method. Unwanted by-products, e.g. the formation of spiro compounds which cannot be converted to the desired secondary products at a later stage of the synthesis, can cause significant losses of yield. German patent application reference 10049271.1 describes a process for the catalytic reduction of alkyne compounds using a mixture of zinc and at least one ammonium, copper, alkali metal or alkaline earth metal salt.
Other reduction processes are described inter alia in J. Amer. Oil Chem. Soc. 49 (1972) 72, in which triple bonds are reduced to cis double bonds in long-chain conjugated fatty acids with zinc in boiling protic solvents.
The drastic reduction conditions mentioned here are unsuitable for thermally labile compounds.
The reduction of conjugated alkynes in protic solvents is described in Helv. Chim. Acta 58 (1975) 1016. The reducing agent used by the authors is zinc dust activated by the addition of potassium cyanide.
On the one hand, the abovementioned methods give only moderate yields; on the other hand, activation with potassium cyanide carries a considerable health risk
The paper in Journal fxc3xcr praktische Chemie 336 (1994) 714-715 contains a method for the (Z)-selective reduction of conjugated triple bonds with a combination of Zn and (Cu/Ag) in polar protic solvents, e.g. methanol/water.
This process has the disadvantage that the reagent is very expensive to prepare and moreover always has to be freshly prepared.
It was therefore an object of the present invention to provide a process for the partial reduction of alkyne compounds which avoided the abovementioned disadvantages of the state of the art.
We have found that this object is achieved by a process for the preparation of cyclohexene derivatives of general formula I or II: 
in which the substituents R1 and R2 independently of one another are defined as follows: 
R2 is OH or a protecting group convertible to a hydroxyl group by hydrolysis,
R3 and R4 are hydrogen or C1-C4-alkyl, and
R5 is hydrogen or C1-C4-acyl,
by the reduction of alkyne compounds of general formula III or IV: 
in which the substituents R1 and R2 are as defined above, wherein the reducing agent used is at least one salt of hyposulfurous acid or hydroxymethanesulfinic acid, or a mixture of at least one salt of hyposulfurous acid and at least one salt of hydroxymethanesulfinic acid.
Alkyl radicals R3 and R4 which may be mentioned are linear or branched C1-C4-alkyl chains, e.g. methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl. Preferred alkyl radicals are methyl and ethyl.
The radicals R3 and R4, together with the carbon atom to which they are bonded, can also form a cycloheptyl or cyclohexyl ring.
Substituents R5 which may be mentioned are linear or branched C1-C4-acyl chains, e.g. formyl, acetyl, propionyl and isopropionyl. The preferred acyl radical is acetyl.
Suitable protective groups R2 convertible to a hydroxyl group by hydrolysis are functional groups which can be converted to the hydroxyl group relatively easily. Examples which may be mentioned are ether groups such as 
silyl ether groups such as xe2x80x94Oxe2x80x94Si(CH3)3, xe2x80x94Oxe2x80x94Si(CH2CH3)3, xe2x80x94Oxe2x80x94Si(isopropyl)3, xe2x80x94Oxe2x80x94Si(CH3)2(tert-butyl) and xe2x80x94Oxe2x80x94Si(CH3)2(n-hexyl), or substituted methyl ether groups such as the xcex1-alkoxyalkyl ether groups of the formulae 
and suitable pyranyl ether groups such as the tetrahydropyranyloxy group and the 4-methyl-5,6-dihydro-2H-pyranyloxy group.
For R2 it is particularly advantageous to use the tetrahydropyranyloxy group: 
or the xcex1-ethoxyethoxy group of the formula 
Conditions for cleavage of the abovementioned protective groups can be found inter alia in T. Greene xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, John Wiley and Sons, 1981, Chapter 2.
Within the framework of the present invention, salts of hyposulfurous acid are to be understood as meaning compounds of the general formula MI2(O2Sxe2x80x94SO2), in which MI is a monovalent metal, said salts preferably being sodium dithionite, potassium dithionite or zinc dithionite. Sodium dithionite may be mentioned as a particularly preferred salt in this group.
Suitable salts of hydroxymethanesulfinic acid [HOxe2x80x94CH2xe2x80x94S(xe2x95x90O)OH] are preferably sodium formaldehydesulfoxylate or zinc formaldehydesulfoxylate, especially sodium formaldehydesulfoxylate.
In one preferred embodiment of the process according to the invention, the reducing agent used is a mixture of at least one salt of hyposulfurous acid and a base selected from the group comprising sodium carbonate, sodium hydrogencarbonate, potassium carbonate and potassium hydrogencarbonate. A combination of sodium dithionite and NaHCO3 has proved to be a particularly advantageous reducing agent.
Blankit(copyright) (BASF Aktiengesellschaft), a reducing bleach based on sodium dithionite and sulfinic acid, is also suitable.
The following reducing agents can also be used:
calcium hydroxymethanesulfinate,
sulfoxylic acid compounds of other aldehydes such as acetaldehyde, benzaldehyde and butylaldehyde, and formamidinesulfinic acid.
The present invention further relates to a process for the preparation of cyclohexene derivatives of formula I or II wherein sodium dithionite is formed in situ, e.g. by the so-called formate process, where sodium formate is reacted with sodium hydrogensulfite in 80% methanol, the pH is then adjusted to approx. 9.5 by the addition of a base, and the agent to be reduced is then introduced into the reaction mixture.
Sodium dithionite can also be formed in situ via the so-called borol process by reacting sodium hydridoborate with sodium hydroxide solution and sulfur dioxide.
It has been found that the reduction according to the invention proceeds particularly well in the presence of water. The amount of water is chosen so that the base and the reducing agent are present in dissolved form. As a rule, a total of 600 to 4000 ml of water, particularly preferably 800 to 1600 ml of water, are used per mole of base introduced and per mole of reducing agent.
The addition of an inert solvent has also proved advantageous for the reduction process.
Suitable inert solvents in the process according to the invention are generally any solvents inert towards the compounds I to IV. The reaction is preferably carried out in chlorinated hydrocarbons, e.g. dichloromethane, perchloroethylene or chloroform, or in an ethereal solvent such as a dialkyl ether, tetrahydrofuran or dioxane, especially in the water-immiscible methyl tert-butyl ether. Other suitable solvents are aromatic hydrocarbons, especially toluene, and C1-C3-alcohols such as methanol, ethanol or propanol.
It is preferred to use a 10 to 70% by weight solution of the alkynediol in one of the abovementioned solvents and particularly preferred to use a 30 to 65% by weight solution of the alkynediol in methylene chloride.
The reduction proceeds in a pH range of 6.0 to 10, preferably of 7.8 to 9.
The sodium dithionite is used in an amount of about 1.1 to 5 gram atoms, preferably of 1.5 to 4 gram atoms and particularly preferably of 2.1 to 3 gram atoms per mole of alkynediol to be reduced. To be able to observe the pH range of 6.0 to 10 during the reduction process, 0.1 to 4 mol of base, preferably 1 to 3.5 mol of base, are used per mole of sodium dithionite.
The reduction can be carried out at temperatures between room temperature and the boiling point of the solvent used.
Preferred reaction temperatures range from 30 to 100xc2x0 C., particularly preferably from 40 to 80xc2x0 C.
In one particularly preferred variant of the process according to the invention, the reduction is carried out continuously, for example by reacting the reaction mixture, preferably consisting of alkynediols of formula IIIa or IVa, an organic solvent, water, a base and a reducing agent, in a tubular reactor or a series of stirred-tank reactors at elevated temperatures ranging from 30 to 100xc2x0 C.
The process according to the invention is particularly suitable for the preparation of the cyclohexene compounds of formulae Ia and IIa: 
The general procedure for carrying out the process is successively to introduce water, base and alkyne compounds (in the case of the cyclohexene compounds of formulae Ia and IIa, alkyne compounds of formula IIIa or IVa, dissolved in an inert solvent, are used): 
and finally to introduce the reducing agent, either in portions or all at once.
The subject of the present invention will be illustrated in greater detail with the aid of the following Examples.